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ZFIN ID: ZDB-PUB-110901-1
Disc1 regulates both β-catenin-mediated and noncanonical Wnt signaling during vertebrate embryogenesis
De Rienzo, G., Bishop, J.A., Mao, Y., Pan, L., Ma, T.P., Moens, C.B., Tsai, L.H., and Sive, H.
Date: 2011
Source: FASEB journal : official publication of the Federation of American Societies for Experimental Biology   25(12): 4184-97 (Journal)
Registered Authors: De Rienzo, Gianluca, Ma, Taylur, Moens, Cecilia, Pan, Luyuan, Sive, Hazel
Keywords: Disc1, zebrafish, brain, neurons, G5K3β
MeSH Terms:
  • Amino Acid Sequence
  • Animals
  • Animals, Genetically Modified
  • Base Sequence
  • Binding Sites
  • Brain/embryology
  • Brain/metabolism
  • Conserved Sequence
  • DNA Primers/genetics
  • Embryonic Development/genetics
  • Embryonic Development/physiology
  • Glycogen Synthase Kinase 3/metabolism
  • Humans
  • Mutagenesis
  • Nerve Tissue Proteins/antagonists & inhibitors
  • Nerve Tissue Proteins/genetics
  • Nerve Tissue Proteins/metabolism*
  • Neurogenesis/genetics
  • Neurogenesis/physiology
  • Oligodeoxyribonucleotides, Antisense/genetics
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Species Specificity
  • Wnt Signaling Pathway*
  • Zebrafish/embryology*
  • Zebrafish/genetics
  • Zebrafish/metabolism*
  • Zebrafish Proteins/antagonists & inhibitors
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
  • beta Catenin/metabolism*
PubMed: 21859895 Full text @ FASEB J.
FIGURES
ABSTRACT

Disc1 is a schizophrenia risk gene that engages multiple signaling pathways during neurogenesis and brain development. Using the zebrafish as a tool, we analyze the function of zebrafish Disc1 (zDisc1) at the earliest stages of brain and body development. We define a “tool” as a biological system that gives insight into mechanisms underlying a human disorder, although the system does not phenocopy the disorder. A zDisc1 peptide binds to GSK3β, and zDisc1 directs early brain development and neurogenesis, by promoting β-catenin-mediated Wnt signaling and inhibiting GSK3β activity. zDisc1 loss-of-function embryos additionally display a convergence and extension phenotype, demonstrated by abnormal movement of dorsolateral cells during gastrulation, through changes in gene expression, and later through formation of abnormal, U-shaped muscle segments, and a truncated tail. These phenotypes are caused by alterations in the noncanonical Wnt pathway, via Daam and Rho signaling. The convergence and extension phenotype can be rescued by a dominant negative GSK3β construct, suggesting that zDisc1 inhibits GSK3β activity during noncanonical Wnt signaling. This is the first demonstration that Disc1 modulates the noncanonical Wnt pathway and suggests a previously unconsidered mechanism by which Disc1 may contribute to the etiology of neuropsychiatric disorders.

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